AmERICAN ASSOCIATION Of ClINICAl ......2 AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1)WRITING COMMITTEE Cochairpersons Martha A. Zeiger, MD, FACS, FACE

ENDOCRINE PRACTICE Vol 15 (Suppl 1) July/August 2009 1

AACE/AAES Guidelines

© 2009 AACE.

AmERICAN ASSOCIATION Of ClINICAl ENDOCRINOlOgISTSAND AmERICAN ASSOCIATION Of ENDOCRINE SuRgEONS

mEDICAl guIDElINES fOR ThE mANAgEmENTOf ADRENAl INCIDENTAlOmAS

Martha A. Zeiger, MD, FACS, FACE; Geoffrey B. Thompson, MD, FACS, FACE;Quan-Yang Duh, MD, FACS; Amir H. Hamrahian, MD, FACE;

Peter Angelos, MD, PhD, FACS, FACE; Dina Elaraj, MD;Elliot Fishman, MD; Julia Kharlip, MD

The American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas are systematically developed statements to assist health care providers in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and indi-vidual circumstances.

2 AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1)

WRITING COMMITTEE

CochairpersonsMartha A. Zeiger, MD, FACS, FACE

Geoffrey B. Thompson, MD, FACS, FACEQuan-Yang Duh, MD, FACS

Amir H. Hamrahian, MD, FACE

Primary WritersMartha A. Zeiger, MD, FACS, FACE

Geoffrey B. Thompson, MD, FACS, FACEQuan-Yang Duh, MD, FACS

Peter Angelos, MD, PhD, FACS, FACEDina Elaraj, MD

Elliot Fishman, MDAmir H. Hamrahian, MD, FACE

Julia Kharlip, MD

REVIEWERS

American Association of Clinical Endocrinologists ReviewersJeffrey R. Garber, MD, FACP, FACE

Jeffrey I. Mechanick, MD, FACP, FACE, FACN

American Association of Endocrine Surgeons ReviewersMichael J. Demeure, MD, MBA, FACS, FACE

William B. Inabnet, MD, FACS

AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1) �

Abbreviations:AACE = American Association of ClinicalEndocrinologists; AAES =AmericanAssociation ofEndocrine Surgeons; ACC = adrenocortical carci-noma;ACE=angiotensin-convertingenzyme;ACTH= adrenocorticotropic hormone; APA = aldosterone-producing adenoma; ARBs = angiotensin II recep-torblockers;ARR=aldosterone-to-reninratio;AVS= adrenal venous sampling; BEL = “best evidence”ratinglevel;CT=computedtomographic;EL=evi-dence level; FDG = fludeoxyglucose; FNA = fine-needleaspiration;HPA=hypothalamic-pituitary-adre-nal;HU = Hounsfield units; IHA=bilateralidiopathichyperaldosteronism;MRI=magneticresonanceimag-ing;PAC=plasmaaldosteroneconcentration;PAH=primaryadrenalhyperplasia;PET=positronemissiontomography;PRA=plasma reninactivity;R= rec-ommendation;SCS=subclinicalCushingsyndrome;UFC=urinefreecortisol

1. INTRODUCTION

Theincidenceofadrenalincidentaloma,atermcoinedinreferencetothephenomenonofdetectinganotherwiseunsuspectedadrenalmassonradiologicimaging,hasbeenincreasingandnowapproachesthe8.7%incidencereportedinautopsyseries (1 [evidence levelorEL 3], 2 [EL 3]).The definition of incidentaloma excludes patients undergo-ingimagingproceduresaspartofstagingandwork-upforcancer.Notonlyaremore incidentalomasbeingdetectedby imaging but they are increasingly more likely to befunctional because of the more common evaluations forsubclinical syndromes (3 [EL 2]). During the evaluationofanadrenalmass,3questionsneedtobeaddressed:(1)Is the tumor hormonally active? (2) Does it have radio-logiccharacteristicssuggestiveofamalignantlesion?and(3) Does the patient have a history of a previous malig-nant lesion?Thepatientshouldbe testedforevidenceofhypercortisolism,aldosteronism(ifhypertensive),andthepresenceofapheochromocytoma.Asummaryof the lit-erature revealed that approximately 80% of patients with incidentalomas had a nonfunctioning adenoma, 5% hadsubclinicalCushingsyndrome(SCS),5%hadapheochro-mocytoma,1%hadanaldosteronoma,<5%hadanadre-nocortical carcinoma (ACC), and 2.5% had a metastaticlesion; the remaining incidentalomaswereganglioneuro-mas,myelolipomas,orbenigncysts(4 [EL 4], 5 [EL 4]). Before consideration of surgical resection, a highdegreeofcertaintyofthediagnosisiscriticalandcanbeachieved with a combination of biochemical and radio-graphic studies. Patients who present with an adrenalincidentalomashouldbereferredtoanendocrinologistorendocrine surgeon for assessment. Pheochromocytomas

necessitatecarefulpreoperativepreparationtoavoidintra-operative and postoperative morbidity and mortality. Inpatients with primary aldosteronism, a thorough evalua-tionshouldbeperformedtoensurethattheydonothaveadrenocortical hyperplasia and a nonfunctioning adrenaladenoma.PatientswithadrenalCushingsyndromedevelopadrenal insufficiency after resection and will require steroid coverageandcarefulwithdrawal.WhetherthosewithSCSrequiresurgicaltreatmentiscontroversial.ThosepatientswithACC requirepreoperativeplanning in collaborationwith an endocrinologist or oncologist because the effec-tiveness of the initial resection can be a major predictorof survival. Finally, nonfunctioning adrenal tumors ≥4 cm (Fig.1)shouldbeconsideredforsurgicalresection.Incon-trast,smallmyelolipomas,benigncysts,ornonfunctioningadenomas can be diagnosed with considerable certaintyand usually do not necessitate surgical resection unlesssymptomatic. Depending on the clinical circumstances,resectionmaybeindicated. Theonlypreviouslypublishedclinicalpracticeguide-linesonthemanagementofpatientswithadrenalinciden-talomas originated from a National Institutes of Healthconsensus conference and was published in 2002 (6 [EL 4]). This current set of clinical practice guidelines sum-marizes the relevant literatureas itpertains to thediffer-entialdiagnosis,laboratoryandradiologicevaluation,andclinicalmanagementandincludesrecommendations(eachlabeled“R”inthesubsequentsection)basedonthe“bestevidence”ratinglevel(BEL)ofthepublishedsources.

2. ExECUTIVE SUMMARy OF RECOMMENDATIONS

• R1. Patients with an adrenal incidentaloma shouldundergoevaluationclinically,biochemically,andradio-graphicallyforsignsandsymptomsofhypercortisolism,aldosteronism(ifhypertensive),thepresenceofapheo-chromocytoma,oramalignanttumor(Grade C; BEL 3).

• R2.Patientswithadrenalincidentalomaswhodonotful-fill the criteria for surgical resection need to have radio-graphicreevaluationat3to6monthsandthenannuallyfor1to2years.Foralladrenaltumors,hormonalevalu-ationshouldbeperformedatthetimeofdiagnosisandthenannuallyfor5years(Grade C; BEL 3).

• R3. All patients found to have an incidental adrenalmass should be screened for cortisol excess. Although thebeststrategyforpatientswithincidentalomashasnotbeenestablished,thesimplestscreeningtestforautono-mouscortisolsecretionfromanincidentalomaisa1-mgovernight dexamethasone suppression test. If clinical suspicionishigh,suchasinpatientswithhypertension,obesity,diabetesmellitus,orosteoporosis,3tests(sali-

� AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1)

vary cortisol, dexamethasone suppression, and urine free cortisol[UFC])canbeused(Grade C; BEL 3).

• R4.After adrenalectomy for a cortisol-producing ade-noma, patients should be treated with exogenous gluco-corticoidsuntilthehypothalamic-pituitary-adrenal(HPA)axis has recovered. This process may take 6 to 18 months afterunilateraladrenalectomy(Grade C; BEL 3).

• R5.AdiagnosisofSCSismadeiftheserumcortisollevelis more than 5.0 mg/dL after a 1-mg dexamethasone sup-pressiontest,inapatientwithanadrenaladenomaandabsenceoftypicalphysicalstigmasofhypercortisolism.A lowor suppressed levelof adrenocorticotropichor-mone(ACTH)oralowdehydroepiandrosteronesulfateconcentration supports the diagnosis (Grade D; BEL 4). A second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone suppression test,mayalsobeneeded to establish thediagnosisofSCS (Grade B; BEL 2).

• R6.InpatientswithSCS,untilfurtherevidenceisavail-able regarding the long-term benefits of adrenalectomy, surgical resection should be reserved for those with

worseningofhypertension,abnormalglucosetolerance,dyslipidemia,orosteoporosis(Grade D; BEL 4).

• R7. Perioperative glucocorticoid therapy and postop-erative assessment of HPA axis recovery are indicated inpatientswithSCS(Grade C; BEL 3).

• R8. Patients thought to have a pheochromocytomashould undergo measurement of plasma fractionatedmetanephrines and normetanephrines or 24-hour total urinarymetanephrinesandfractionatedcatecholamines(orbothplasmaandurinestudies)(Grade A; BEL 1).

• R9.Aboutone-quarterofpatientswithapheochromo-cytomawillhaveassociatedfamilialsyndromescausedbymutationsintheRETgene(multipleendocrineneo-plasiatype2),VHLgene(vonHippel-Lindaudisease),or succinate dehydrogenase genes; genetic study andcounseling shouldbeperformed,especially foryoungpatients or patients with an extra-adrenal pheochromo-cytoma(Grade C; BEL 3).

• R10. Surgical resection should be performed for allpheochromocytomas(Grade C; BEL 3).

Fig. 1.Algorithmfortheevaluationandmanagementofanadrenalincidentaloma.*=Reimagein3to6monthsandannuallyfor1to2years;repeatfunctionalstudiesannu-allyfor5years.Ifmassgrowsmorethan1cmorbecomeshormonallyactive, thenadrenalectomyisrecommended.CT=computedtomographic;HU = Hounsfield units; PAC=plasmaaldosteroneconcentration; PRA=plasmareninactivity.

AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1) 5

• R11. In all patients with a pheochromocytoma, anα-adrenergicblockingagentshouldbeadministeredpre-operatively,inanefforttopreventintraoperativehemo-dynamicinstability(Grade C; BEL 3).

• R12. In patients who have undergone resection of apheochromocytoma, long-term follow-up is necessarybecause 10% to 15% may have recurrence (Grade B; BEL 2).

• R13.Screeningforaldosteronismshouldbeperformedinpatientswithanaldosterone-to-reninratio(ARR)of>20 (Grade C; BEL 3).

• R14. Primary aldosteronism is confirmed in the setting of an adrenal incidentalomabydemonstrating lackofaldosterone suppression (24-hour urine study) with salt loading(Grade C; BEL 3).

• R15.Subtypeevaluationshouldbeachievedwithhigh-resolution computed tomographic (CT) scanning inallpatientsandadrenalvenoussampling(AVS)inthemajority of patients older than 40 years (Grade C; BEL 3).

• R16.Inpatientswithprimaryaldosteronismandauni-lateral source of aldosterone excess, laparoscopic total adrenalectomy is the treatment of choice because ityields excellent outcomes with low associated morbid-ityrelativetoopenapproaches(Grade C; BEL 3).

• R17.Patientswithbilateralidiopathichyperaldosteron-ism (IHA)or thosenot amenableor agreeable to sur-gical intervention should be managed with selectiveand nonselective mineralocorticoid receptor blockers(Grade A; BEL 1).

• R18.Any adrenal mass with concerning radiographiccharacteristics and most lesions ≥4 cm should be resected because of increased risk of adrenal cancer(Grade C; BEL 3).

• R19. The presence of pheochromocytoma should beruledoutbiochemicallybeforeanattempted resectionofanyadrenalmass(Grade C; BEL 3).

• R20.AllpatientssuspectedofhavinganACCshouldundergobiochemicalevaluationtoidentifyanypoten-tial hormone excess that serves as a tumor marker and to determinewhetherthepatientrequiressteroidreplace-ment perioperatively in cases of hypercortisolism(Grade D; BEL 4).

• R21.OpenadrenalectomyshouldbeperformedifACCissuspected(Grade C; BEL 3).

• R22.Ametastaticlesionshouldbesuspectedinapatientwithahistoryofcancerandanadrenalmassthatdoesnot fulfill the criteria for an incidentaloma (Grade C; BEL 3).

• R23. In very rare instances, pathologic confirmation withCT-guidedneedlebiopsymayberequiredforstag-ing and planning of oncologic treatments (Grade D; BEL 4).

• R24. The presence of pheochromocytoma should beruledoutwithbiochemicaltestingbeforeperformanceofabiopsy(Grade C; BEL 3).

• R25. Patientswithbilateral adrenalmetastatic lesionsshould undergo evaluation for adrenal insufficiency (Grade D; BEL 4).

• R26. Adrenal metastasectomy is rarely indicated butshouldbeconsideredinthecaseofanisolatedadrenalmetastaticlesion(Grade C; BEL 3).

3.METHODS FOR DEVELOPMENT OF THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN ASSOCIATION OF ENDOCRINE SURGEONS MEDICAL GUIDELINES FOR THE MANAGEMENT OF ADRENAL INCIDENTALOMAS

In 2004, the American Association of Clinical Endocrinologists (AACE) Protocol for StandardizedProductionofClinicalPracticeGuidelineswaspublishedin Endocrine Practice (7 [EL 4]). Those recommenda-tionswereusedforthepreparationofthisdocument.TheAmericanAssociationofEndocrineSurgeons(AAES)andAACE cochairpersons and primary writers are experts in theclinicalmanagementofadrenaldiseases.After thecompletion of the first draft created by the primary writers, thechairpersonsreviewedthetechnicalassignmentofevi-dence levels (inserted in the reference list and in the text) and recommendation grades (in the Executive Summary). The document was subsequently reviewed by theAAESand AACE publication and executive committees and then finally completed by the chairpersons.

4. ADRENAL INCIDENTALOMA

4.1. History and Physical Examination Patients who have an adrenal incidentaloma identi-fied on CT or magnetic resonance imaging (MRI) need to undergoathoroughclinicalevaluation.Thehistoryshouldbe aimed at excluding a functional tumor. For patients with hypercortisolism or Cushing syndrome, the investigationshould include inquiries about substantial weight gain


or development of centripetal obesity, easy bruisability,severe hypertension, diabetes, virilization, proximal mus-cleweakness,orfatigue.Forpatientswithpheochromocy-toma,inquiriesshouldaddressthedevelopmentofsuddenor severe headaches, weight loss, anxiety attacks, sweat-ing,cardiacarrhythmias,orpalpitations.Forpatientswithaldosteronism,theclinicianshouldaskaboutthepresenceof hypertension, fluid retention, or a history of hypokale-mia.Theclinicianshouldinquireaboutahistoryofcancer,recentweightloss,andasmokinghistorybecauseanadre-nal mass may be a metastatic lesion. Physical examination should include measurement of the patient’s blood pres-sureandpulseaswellasassessmentforevidenceofcentralobesity,ecchymoses,striae,musclewasting,hirsutism,orothersignsofvirilization.Areviewofphotographstakenoverseveralyears,suchasthoseonadriver’slicense,maymakechangesinappearanceobvious.

4.2. Biochemical Evaluation The detection of an adrenal lesion should promptbiochemical evaluation unless it is an obvious myeloli-poma.Adrenal myelolipomas are of low CT attenuationandalsocontainfat(-10 to -20 Hounsfield units [HU]); therefore,thediagnosisisgenerallyclear(8 [EL 2]).Anyhormonallyhyperfunctioningadenomaneedstobesurgi-callyresected.PatientsarescreenedforSCSwitha1-mgovernight dexamethasone suppression test. A diagnosis of SCS is suspected if the serum cortisol level exceeds 5.0 mg/dL after a 1-mg dexamethasone suppression test. A low orsuppressedlevelofACTHoralowdehydroepiandros-teronesulfateconcentrationfurthersupportsthediagnosis.A second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone suppression test, may be needed to establish the diagnosis of SCS (9 [EL 2]).Patients with hypertension who have a ratio of plasmaaldosteroneconcentration(PAC)(ng/dL) toplasmareninactivity (PRA) (ng/mL per hour) of >20 while not taking spironolactone and mineralocorticoid receptor blockersshouldundergofurtherassessmentforthepresenceofpri-maryaldosteronism(4 [EL 4], 10 [EL 4]).Finally,elevatedplasmafreemetanephrineandnormetanephrinelevelsand24-hour total urinary metanephrines and fractionated cat-echolaminessuggestthepresenceofapheochromocytoma(11 [EL 4], 12 [EL 3]).Ingeneral,testingthepatientforthe production of excess sex hormones is not indicated unlessthepatienthasobviousclinicalstigmas.

4.3. Radiologic Imaging Theprimarygoalofimagingistodistinguishamongadrenaladenoma,adrenalcarcinoma,pheochromocytoma,and metastatic lesions. It is important to emphasize thatimaging cannot reliably distinguish between functioningand nonfunctioning adrenal adenomas. The diagnosis ofanadenomareliesonthepresenceofintracellularlipidinthe adrenal lesion, which can be identified by density mea-

surementonnoncontrastCTorin-phaseandout-of-phaseMRI. Alternatively, an adenoma can be identified by mea-suringcontrast-washoutkineticsonCT.Lesionsthathavean attenuation value below 10 HU on noncontrast CT scan areadenomas(8 [EL 2], 13 [EL 3], 14 [EL 3]).Adenomasconstitute about 70% of adrenal masses seen in the clinical setting. ThedifferentialdiagnosiscanbefurtherdelineatedbyCTscansdoneimmediatelyafterintravenousadministra-tion of a contrast agent and then again after a 10- to 15-min-utedelay.Benignadrenallesionswillcommonlyenhanceup to 80 to 90 HU and wash out more than 50% on the delayedscan,whereas lesionssuchasmetastatic tumors,carcinomas, or pheochromocytomas will not (8 [EL 2]).Pheochromocytomas usually show enhancement to morethan 100 HU, diagnostically separating them from adeno-mas.OnnoncontrastCT,somebenignadrenallesionsdonot have attenuation values of less than 10 HU and may have values of 20 to 40 HU. This result is found in lipid-poor adenomas. In these cases, a washout of >50% will oftenallowthediagnosisofanadenomatobemade.Thisobservation, however, needs to be confirmed with larger studies.

4.4. Follow-up of Patients With a Nonfunctioning Adrenal Incidentaloma Patients with adrenal incidentalomas smaller than 4 cmandradiologiccharacteristicsconsistentwithabenignadenomaneedtohaveradiographicreevaluationat3to6monthsand thenannually for1 to2years (6 [EL 4], 15 [EL 3], 16 [EL 3]).Hormonalevaluationshouldbeper-formedatthetimeofdiagnosisandthenannuallyforupto5years(3 [EL 2]).Theriskofthemassenlargingduring1,2, and 5 years is 6%, 14%, and 29%, respectively, and the riskofthemassbecominghormonallyactiveduringthosetime periods is 17%, 29%, and 47%, respectively (3 [EL 2]).Themostcommonhormonallyactivelesioninpatientswithpreviously inactiveadenomas isSCS.The rateofabenignadenomaorhyperplasiadevelopingintoanACCisnot well known, but such a change seems to be extremely rare (15 [EL 3], 17 [EL 2], 18-20 [EL 3]). Should thetumorgrowmorethan1cmorbecomehormonallyactiveduring follow-up, surgical excision should be considered. Currently,itisunclearwhattherecommendationsshouldbeafter5yearsoffollow-upforastable,nonfunctioningadrenalmass.

5. CORTISOL-PRODUCING ADRENAL ADENOMA

5.1. Overview AdrenocorticaladenomacancausebothovertCushingsyndrome and SCS. Those patients with an incidentalradiographic finding of the adrenal lesion are more likely thanotherstohaveSCS.WithbetterunderstandingofSCSandmorefrequenttestingforit(4 [EL 4], 21-23 [EL 4]),

AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1) �

this disease entity is being identified more frequently. Of thehormonallyactiveincidentalomas,thisdiagnosiscon-stitutes the most common form—5.3% of more than 2,000 casesreportedintheworldliterature(4 [EL 4]).Overtclin-icalsignsandsymptomsofCushingdiseasearenotalwayspresent;thus,biochemicaltestingisnecessarytosecurethediagnosis.Overt adrenalCushing syndrome is character-izedbyallthetypicalstigmasofhypercortisolism.

5.2. History and Physical Examination Particular attention should be directed at eliciting ahistoryof fatigue,depression, sleepdisturbances,weightgain,menstrualirregularities,hypertension,glucoseintol-erance,easybruising,orfracturewithminimaltrauma.Onphysical examination, the physician should measure the patient’sbloodpressureandpulseandlookforcentralobe-sity,supraclavicular fataccumulation,adorsocervical fatpad,facialplethora,thinnedskin,purpleandwide(>1cm)striae, acne, ecchymoses, hirsutism, and proximal muscle weaknessorwasting.Changesonphotographstakenoverseveralyears(suchas thoseondriver’s licenses)maybeof particular help.All these signs and symptoms shouldraise the level of suspicion for Cushing syndrome. Many patientswithmildCushingsyndrome,however,willhaveonlyafewofthesesignsandsymptomspresent,andmanypatients without Cushing syndrome may also exhibit one or more of these findings. Therefore, Cushing syndrome cannotbediagnosedonpurelyclinicalgrounds,andacare-fulbiochemicalevaluationisnecessary.

5.3. Biochemical Evaluation for Adrenal Cushing Syndrome BiochemicalevaluationforadrenalCushingsyndromeis a 2-step process that first includes screening with 1 or 2 screening tests. If the screening test results are positive,confirmatory tests are then performed. Testing is based on demonstrating3pathophysiologicderangementstypicalofCushing syndrome: (1) loss of a normal diurnal pattern,with abnormally high late-night cortisol secretion (late-nightsalivarycortisol test); (2) failure todiscontinue theproductionofcortisol,despitetheabsenceofACTHstimu-lation (dexamethasone suppression test); and (3) excess production of cortisol (24-hour UFC test).

5.4. Screening Tests

5.4.1. Late-Night Salivary Cortisol Thelate-nightsalivarycortisoltestisthemostrecentassaytobeusedforscreeningforCushingsyndromeandisnowavailable throughmost laboratories.Patientswitharegularsleeppatterncancollectaspecimenofsalivaatbedtimeathomeandthenbringormailthesamplestothelaboratoryfortesting.SeveralinvestigatorshaveshownthatelevatednighttimecortisollevelsappeartobetheearliestandmostsensitivemarkersforCushingsyndrome(24 [EL

4], 25 [EL 4]), with sensitivity and specificity approaching 90% to 95% (26 [EL 3]).

5.4.2. Overnight 1-mg Dexamethasone Suppression Test The overnight 1-mg dexamethasone suppression test is performed by administration of 1 mg of dexamethasone at 11pmanddeterminationofafastingplasmacortisollevelbetween8am and 9 amthefollowingday.Suppressionoftheplasmacortisollevelto<1.8mg/dLhasthebestnega-tivepredictivevalueforCushingsyndrome(5 [EL 4]).Apositive test result shouldbe followedbyfurther testing,including 24-hour UFC, midnight salivary cortisol, or a 2-day low-dose dexamethasone suppression test.

5.4.3. 24-Hour UFC Because UFC levels are not affected by factors thatinfluence corticosteroid-binding globulin, UFC is a better reflection of cortisol levels than plasma cortisol levels and is an integrated measure of excess production of cortisol. AnelevatedUFClevelwarrantsfurtherinvestigation,anda UFC that is more than 4 times the normal value is con-sidereddiagnosticofCushingsyndrome(27 [EL 4]).Upto3-foldelevationofUFCcanbeassociatedwithpseudo-Cushing syndrome attributable to chronic anxiety, depres-sion, alcoholism, or obesity or can accompany use ofcertainmedications(24 [EL 4], 28 [EL 3]).Thus,furtherconfirmatory testing is needed in such a case. No currently available screening test has a 100% sensitivityandthus,whenusedalone,cannotcompletelyexclude the presence of hypercortisolism. Because these tests targetdifferentaspectsorpathophysiologic featuresof Cushing syndrome, they are complementary in thescreening process.Although the best diagnostic strategyforpatientswithincidentalomashasnotbeenestablished,thesimplestscreeningtestforautonomouscortisolsecre-tion from an incidentaloma is a 1-mg overnight dexameth-asonesuppressiontest.Ifclinicalsuspicionishigh,suchasinpatientswithhypertension,obesity,diabetesmellitus,orosteoporosis, all 3 tests (salivary cortisol, dexamethasone suppression,andUFC)canbeused. A low or suppressed ACTH level would confirm an adrenal origin of Cushing syndrome.The lackofACTHresponseduringthecorticotropin-releasinghormonestim-ulationtestmaybeusedinthosepatientswithborderlineACTHlevelstodistinguishACTH-dependentfromACTH-independentCushingsyndrome(29 [EL 4]).

5.5. Perioperative Management Inpatientswithelevatedcortisollevels,careshouldbeexercised during the preoperative period to ensure that dia-betesandhypertension,ifpresent,aretreatedadequately.Because these patients are at increased relative risk forthromboemboliccomplications,measuresmustbeimple-mentedtopreventthesecomplicationsduringtheperiop-erative period. In the unusual patient with long-standing


and very high levels of cortisol, the presence of severeimmunosuppressionmustbeconsidered,andprophylacticperioperativeantibioticsshouldbeused.Pepticulcerpro-phylaxis should also be provided. PatientswithCushingsyndromealsohaveasuppressedHPA axis. Excess cortisol secretion from an adrenocorti-cal adenoma suppresses the production ofACTH by thepituitary.ThissituationleadstoatrophyofthecontralateraladrenalglandthatisdevoidofthetrophiceffectsofACTH.Once a cortisol-producing adenoma has been removed,physicians must administer glucocorticoid replacementbecausetheremainingadrenalglandissuppressed(30 [EL 3]). High stress doses can usually be weaned to mainte-nance doses of hydrocortisone of approximately 12 to 15 mg/m2(31 [EL 4]).AfteranadrenalsurgicalprocedureforCushingsyndrome,physiciansshouldbepreparedtotreatpatients with exogenous glucocorticoids until the HPA axis hasrecovered.Theamountoftimeforrecoveryvariesfrom6 to18monthsafteraunilateraladrenalectomy.Dohertyetal(32 [EL 2])reportedamediantimeof15monthstorecover a normal response to theACTH stimulation testand 19 months (range, 12 to 24) to allow discontinuation ofhydrocortisone.Duringpreoperative informedconsentdiscussions,allpatientsshouldalsobecautionedabouttheimportanceoflong-termcorticosteroidreplacement.

6. SUBCLINICAL CUSHING SyNDROME

6.1. Overview More than 5% of patients with adrenal incidentalo-masmayhaveSCS(4 [EL 4]). This poorly defined entity maybeuniquetopatientswithadrenalincidentalomas.Itischaracterizedbysubtleautonomousproductionofcorti-solbyanadrenaltumor,whichisusuallyassociatedwithsuppressed production of cortisol from the contralateralglandbutnoovertclinicalfeaturesofCushingsyndromesuch as atypical fat redistribution, skin fragility, or proxi-mal muscle weakness. Ultimately, the best proof for thepresence of this disorder is the development of adrenalinsufficiency postoperatively. It has been postulated that long-term exposure to subtle cortisol excess may lead to the metabolic derangements seen in patients with overtCushing syndrome. Many, although not all, studies found higherprevalencesofhypertension,obesity,insulinresis-tance,dyslipidemia,andosteoporosisinpatientswithSCS(33-36 [EL 3]). Nevertheless, no conclusive evidenceexists for a causal relationship between subtle autonomous productionof cortisol and suchmetabolicderangements.In fact, Reincke (37 [EL 4]) theorized that adrenal nod-ulesmightrepresentamanifestationofthemetabolicsyn-drome and develop because of a trophic effect of excess insulinon theadrenalglands.Little information isavail-ableaboutthenaturalhistoryofthiscondition.IthasbeenshownthatprogressiontoovertCushingsyndromeisarareeventwithin1to7yearsoffollow-up(3 [EL 2], 17 [EL

2]).Otherwise,long-termmorbidityandmortalitydataarelacking.Similarly,therearenolong-termoutcomedataforpatientswhoweretreatedmedicallywithriskfactormodi-fication alone versus those who underwent surgical resec-tionofadrenaladenomas.

6.2. Diagnosis ThediagnosisofSCSismadebiochemically;however,thevariabilityamongdiagnosticcriteriaused in researchstudies is significant. The 1-mg dexamethasone suppres-siontestismoresensitivethanUFCindiagnosingthiscon-dition(29 [EL 4]). An abnormal result of the dexametha-sonesuppressiontestwasthemostcommonbiochemicalabnormalityseeninpatientsundergoingfollow-upbytheStudyGrouponAdrenalTumorsoftheItalianSocietyofEndocrinology(9 [EL 2])andotherswhohavestudiedthecondition. Consequently, the dexamethasone suppression test is themost frequentlyused initialscreening test,butthe appropriate cutoff cortisol level is debated.A cutoffpointof5mg/dL was associated with a specificity of 100% andasensitivityof58%in1study,whereasalowercutoffpointofabout1.8mg/dL had a 75% to 100% sensitivity and a 72% to 82% specificity (38 [EL 3], 39 [EL 3]).Hence,we recommenduseof thehighercutoffpoint (5mg/dL),which has a higher specificity. In addition, because yearly biochemical reevaluation is recommended for 5 years inpatients with nonfunctioning lesions, those patients withfalse-negativeresultsontheinitialevaluationmaybeiden-tified at later reassessment. A low or suppressed level of ACTHor lowdehydroepiandrosteronesulfateconcentra-tion supports the diagnosis of SCS. Some investigatorshave required a second abnormal test result of HPA axis function, such as a 2-day low-dose dexamethasone sup-pression test, to establish the diagnosis of SCS (9 [EL 2]). A consultation with an endocrinologist experienced in interpreting tests of the HPA axis should be sought (29 [EL 4]).

6.3. Management Atthistime,nolong-termprospectivedataareavail-ableforguidanceinthechoicebetweenmedicalandsur-gical therapy for thesepatients.Althoughseveral studiesreportimprovementinindividualcardiovascularriskfac-tors,particularlyhypertension,afteradrenalectomy,mostmetabolic derangements persist. Young (40 [EL 4]) hasproposedacommonsensestrategy tooperateonyoungerpatients (<40 years old) with a recent onset or worsening ofdiabetes,hypertension,orosteoporosis.Inolderpatientswith worsening of clinical comorbidities, clinical judg-mentshouldbeusedaboutreferralforsurgicaltreatment.In all patients undergoing a surgical procedure for SCS,corticosteroid replacementshouldbe initiatedonpostop-erativeday1afterabloodsamplehasbeenobtainedfordeterminationofamorningserumcortisolvalue,andtheyshould be followed until HPA axis functionality is restored,


asoutlinedinthesectiononCushingsyndrome(seesec-tion5.5)(41 [EL 3]).ThereisnoneedforglucocorticoidreplacementintraoperativelyinpatientswithCushingsyn-drome(42 [EL 4], 43 [EL 2]).

7. PHEOCHROMOCyTOMA

7.1. Overview Thepresenceofapheochromocytomashouldbesus-pected in patients with severe hypertension, tachycardia,palpitations, cardiac arrhythmias, anxiety attacks, weight loss,orsweating.About15%ofpatientswithapheochro-mocytoma,however,havenohistoryofhypertension.Themanagementofpatientswithapheochromocytomabeginswith a biochemical diagnosis. Traditionally, biochemi-cal evidence of the disease has been confirmed with 24-hour fractionated catecholamines, vanillylmandelic acid,and total urinary metanephrines. More recently, because ofahighsensitivity rate,plasmafreemetanephrinesandnormetanephrines have been measured. Although theurinary measurements have a higher false-negative rate,theplasmalevelsareassociatedwithahigherfalse-posi-tive rate. Use of tricyclic antidepressants, decongestants,amphetamines, reserpine, and phenoxybenzamine should bediscontinuedtoeliminatethelikelihoodofafalse-posi-tiveresult.Reviewoftheliteraturerevealsnolevelofevi-dence stronger than level 2 to support recommendationsfor themanagementof patientswithpheochromocytoma(44 [EL 4]).

7.2. History and Physical Examination The history should be focused on elicitation of thepresenceof severehypertension,headaches,weight loss,anxiety attacks, sweating, cardiac arrhythmias, or palpita-tionsaswellasafamilyhistoryofsyndromesthatincludepheochromocytomas,suchasvonHippel-Lindaudisease,multiple endocrineneoplasia type2, familialparagangli-oma syndrome, or neurofibromatosis syndromes. Physical examination should include measurement of the patient’s blood pressure and pulse, cardiac examination for conges-tive heart failure, and evaluation for excessive sweating, anxiety, and weight loss.

7.3. Biochemical Evaluation Most pheochromocytomas secrete the catecholamines norepinephrineorepinephrineand,morerarely,dopamine(45 [EL 4]).Traditionally,testingforpheochromocytomahas included a 24-hour urine collection for catecholamines and total or fractionated metanephrines. A 24-hour urine total metanephrine level above 1,800 mgintheappropriateclinicalsettingisalmostalwaysdiagnosticforapheochro-mocytoma, and a plasma metanephrine level exceeding 3 to 4 times normal is highly diagnostic for a pheochromo-cytoma. Reported sensitivities range from 77% to 97%, with specificities from 69% to 98%. Although no single

perfect test is available, themeasurementofplasma freemetanephrinesandnormetanephrineshasthehighestsen-sitivity (97% to 100%) and specificity (85% to 89%) and appearstobethebestinitialtestforscreeningpatientsforpheochromocytoma(11 [EL 4], 12 [EL 3]).

7.4. Genetic Testing In light of the association between certain familialsyndromes and the development of pheochromocytoma,patients diagnosed with pheochromocytomas at a youngage or with multifocal or extra-adrenal disease should be screened with genetic testing for a RET mutation, muta-tionsintheVHLgene,andsubunitsofthesuccinatedehy-drogenasegenes(46 [EL 4], 47 [EL 2], 48 [EL 2]).

7.5. Radiologic Imaging ThesensitivityofCTscanningwithuseofacontrastagent for the diagnosis of pheochromocytoma is 85% to95%, with a specificity of 70% to 100%; the sensitivity of MRI exceeds 95%, with a specificity of 100% (49 [EL 3], 50 [EL 3], 51 [EL 4]). Either may be used as the definitive imagingstudy,dependingonavailability,cost,andpatientpreference. High signal intensity on T2-weighted MRI is highlycharacteristicforpheochromocytoma(52 [EL 4]).

7.6. Malignant Lesion The diagnosis of a malignant tumor is difficult to establishbecausetherearenoreliableradiographicorhis-tologiccriteriatodistinguishbenignfrommalignantpheo-chromocytomas. Malignant pheochromocytoma can be diagnosed if there is extracapsular invasion of the tumor intoadjacentstructuresor ifmetastaticdiseasedevelops.Pheochromocytomas in children, inmen, and in patientswithfamilialsyndromesarelesslikelytobemalignant(53 [EL 4]). Exceptions would be patients with a family his-toryofmalignantpheochromocytomaorwiththesuccinatedehydrogenaseBmutation(54 [EL 3]).

7.7. Preoperative Medical Management Preparationforsurgicaltreatmentincludesα-adrener-gicblockade for1 to3weekspreoperatively inorder toavoid profoundly unstable intraoperative blood pressure.The most commonly used agent is phenoxybenzamine, whichisalong-actingα-adrenergicantagonist.Therapyisstarted at a dosage of 10 mg twice daily, and the dosage is titrated upward to as much as 300 to 400 mg daily in divideddosesuntilthepatientbecomesnormotensive,thehypertensioniswellcontrolled,orintolerablesideeffectsdevelop (orthostatichypotension, tachycardia, nasal con-gestion, nausea, or abdominal pain) (53 [EL 4], 55 [EL 4]).Otherα-adrenergic blocking agents such as doxazo-sin may be used for preoperative preparation of patientswithpheochromocytoma (55 [EL 4]).Alpha-methyltyro-sine (metyrosine), which inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, has


also been used in combination with phenoxybenzamine in the preoperative preparation of patients with pheo-chromocytoma. Small, nonrandomized studies have sug-gestedthatthosepatientswhoreceivethiscombinationofdrugs experience less hemodynamic instability intraop-eratively in comparison with those given phenoxybenza-minealone,butthisresulthasnotbeenvalidatedinlargertrials(56 [EL 3], 57 [EL 3]).Inadditiontoα-adrenergicblockade,patientsaresometimespreparedpreoperativelywithβ-adrenergic blockade. Indications forβ-adrenergicblockade, which should be given only after adequateα-adrenergic blockade, include persistent tachycardia, extra-systoles,orarrhythmias.Propranololisthemostcommonagent used and is administered in dosages of 10 to 40 mg every6to8hours(53 [EL 4]).Calciumchannelblockershavealsobeenusedpreoperativelyandintraoperativelyforblood pressure control.Another important component ofthepreoperativepreparationofthesepatientsisencourag-ing liberal fluid and salt intake, inasmuch as the vasocon-strictedstatethataccompaniespheochromocytomascausesintravascularvolumedepletion.

7.8. Intraoperative Management of Pheochromocytoma Closeintraoperativemonitoringofpatientswithpheo-chromocytoma is imperative, and anesthetic drugs thatprecipitatecatecholaminesecretionshouldbeavoided.Anarteriallineisusedtomonitorbloodpressurecontinuously,andacentralvenouslineisusedtomonitortheintravascu-larvolumestatus.Occasionally,apulmonaryarteriallinemay be necessary in patients with clinically significant car-diacdisease.Inhaledanestheticsthathavetheleastcardiacdepressant effects are generally preferred. Hypertensioncan be controlled with nitroprusside, nicardipine, nitro-glycerin,orphentolamine.Tachyarrhythmiaistreatedwithaβ-adrenergic blocking agent (esmolol), and ventriculararrhythmia is treatedwith lidocaine.Once thepheochro-mocytomahasbeenremoved,thepatientmayhaveseverehypotensionthatnecessitatesuseoflargevolumesofintra-venously administered fluid and α-adrenergic agonists.Becauseof theconsiderable intraoperativehemodynamicchanges that canoccur, it is important that ananesthesi-ologist experienced in the management of pheochromocy-tomas be available. During the immediate postoperativeperiod,patientsshouldbemonitoredforhypotensionandhypoglycemia.

7.9. Postoperative Management and Follow-up Thepostoperativemanagementofpatientswithpheo-chromocytomawilldependonwhetherthetumorisbenignormalignantaswellaswhetherthetumorhasbeencom-pletely resected or just debulked. Because there are nodefinitive diagnostic criteria for malignant pheochromocy-toma,patientswithanapparentlybenignpheochromocy-

toma who have undergone a complete surgical resectionshouldhaveatleastannualfollow-uppostoperatively.Onelarge study found that, in 29 of 176 patients (16%) with an apparentlybenigntumor,recurrentdiseasedevelopeddur-inglong-termfollow-upwithbiochemicaltesting(58 [EL 3]).Patientsinwhomthetumorwasincompletelyresected,orthosewhoseprimarytumorwasresectedbutwhohaveknownmetastaticdisease,shouldcontinuetheirα-adrener-gicblockadetherapypostoperativelyforsymptomcontrol.Antihypertensiveagentsshouldbewithheldafterresectionof localized benign-appearing pheochromocytomas andusedonlyifthepatientappearstohaveunderlyingessen-tialhypertension.Iflong-termtreatmentwithaβ-adrener-gicblockingagenthasbeenused,itshouldnotbestoppedabruptly, especially inolder patientswith ischemicheartdisease.

8. ALDOSTERONOMA

8.1. Overview Onepercentofadrenalincidentalomasareassociatedwith autonomousproductionof aldosterone (59 [EL 3]).Drugresistanceandrefractoryhypertension(needfor>3antihypertensiveagents)arecommonhallmarksofprimaryaldosteronismattributabletoanaldosteronoma,alongwithspontaneoushypokalemia(serumpotassium<3.5mEq/L)or severe (<3 mEq/L) diuretic-induced hypokalemia. Ofnote,mostpatientswithprimaryaldosteronismdonothavehypokalemia(60 [EL 3]). Muscle cramping and weakness, headaches, intermittent or periodic paralysis, polydipsia,polyuria,andnocturiaarelesscommonsymptomsandaregenerally attributable to the degree of hypokalemia (61 [EL 3], 62 [EL 3]). Inadditiontoanaldosteronoma,otherimportantrarecausesofprimaryaldosteronisminthesettingofanadre-nal incidentaloma include primary (unilateral) adrenalhyperplasiaandpurealdosterone-secretingACC(63 [EL 3], 64 [EL 3], 65 [EL 4]).Primaryunilateraladrenalhyper-plasiaisanimportantentitybecauseitsproperrecognitionandsurgicaltreatmentcanleadtocureoforconsiderableimprovement in hypertension. These variations demon-strate a continuumbetweenadrenal adenomaandhyper-plasia, emphasizing the importance of AVS for subtypeevaluation(66-68 [EL 3]).

8.2. Pathology Adenomasareusuallysolitarybut,onrareoccasions,may be bilateral. They are usually less than 2.0 cm in diam-eter, with a mean diameter ranging from 1.5 to 2.0 cm (69 [EL 4]).Typically,primaryunilateraladrenalhyperplasiaischaracterizedbymicronodularormacronodularhyper-plasia andmayconfound thediagnosis inolderpatients,inasmuchasnonfunctioningcorticalincidentalomasoccurwith increasing frequency in patients older than 40 years.


8.3. Diagnosis and Screening DeterminingtheratioofPAC(ng/dL)toPRA(ng/mLper hour) has become the accepted screening modalityforprimaryaldosteronism(65 [EL 4], 70-73 [EL 2], 74-76 [EL 4]).TheadditionofelevatedPACtoahighARRhas increased its specificity as a screening test for primary aldosteronism(4 [EL 4], 10 [EL 4]).Onestudyfoundthatan ARR of more than 30 in conjunction with a PAC value greater than 20 ng/dL had a sensitivity and specificity of 90% and 91%, respectively (73 [EL 2]). Investigators atthe Mayo Clinic (4 [EL 4], 10 [EL 4], 77 [EL 2]) foundthat an ARR greater than 20 in association with a PAC of morethan15ng/dLwashighlysensitive(Fig.2);however,others have reported lower aldosterone levels in patientswithprimaryaldosteronism(78 [EL 4], 79 [EL 2], 80 [EL 2]).Ratioscanbelaboratorydependent.Beforescreening,itisnecessarytowithholdspironolactoneandeplerenone(mineralocorticoid receptor blockers) for 4 to 6 weeks. Diureticsoftenleadtohypokalemia,andinhibitionoftherenin-angiotensinsystemisseenwithangiotensin-convert-ingenzyme (ACE) inhibitorsandangiotensin II receptorblockers(ARBs).AlowPRAinthesettingofanARBorACEinhibitorshouldalertonetothepossibilityofautono-mous aldosterone excess. Thiazide diuretics, calcium chan-nelblockers(dihydropyridines),ACEinhibitors,andARBs

canactuallyimprovethediagnosticdiscriminatorypoweroftheARR;incontrast,β-adrenergicblockingagentsandclonidinesuppressPRAandthusmaycausefalse-positiveresults.TheARRismostsensitivewhenbloodsamplesarecollected in themorning, afterpatientshavebeenoutofbedforatleast2hoursandhavebeenseatedfor5to15minutes.

8.3.1. Confirmation of Primary Aldosteronism The presence of primary aldosteronism can be con-firmed by demonstrating lack of suppression of aldosterone levelsaftersaltloading.Thiscanbedonein1ofthefol-lowingways:(1) patients are instructed to add 1 flat tea-spoonofsalttotheirdailyfoodintakeandtoconsumesaltyfoods (for example, potato chips, pretzels, and pickles) for 72hoursor(2)performanceofthesalinesuppressiontest:isotonic saline is infused at a rate of 300 to 500 mL/h for 4 hours (caution should be exercised in patients with severe hypertension, those receiving multiple antihypertensivemedications, or those with heart failure).A PAC is thendetermined in the seated patient; a nonsuppressed PACexceeding 10 ng/dL is confirmatory of primary aldoste-ronism (81 [EL 3]). During the third day, a 24-hour urine collectionisperformedforaldosterone,sodium,andcreati-ninemeasurement(thelatter2toverifyadequatesaltload-

Fig. 2.Algorithmshowinguseofplasmareninactivity(PRA)andplasmaaldo-steroneconcentration(PAC)andtheirratio(PAC/PRA)fordiagnosingaldosteron-ism in patients with resistant hypertension, hypokalemia, or both. Modified with permissionfromYoungetal(77 [EL 2]).


ing [>200 mEq of sodium per 24 hours] and an adequate [true 24-hour] urine collection). In some medical centers, thepotassiumsupplementiswithheldatthebeginningofthesalt-loadingtest.Themeasurementofpotassiumintheurine during salt loading further supports the diagnosisby demonstrating inappropriate potassium excretion: >30 mmol/d. Failure to suppress 24-hour urinary aldosterone levelstolessthan12mg is confirmatory of primary aldo-steronism(10 [EL 4], 65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).

8.3.2. Aldosterone-Producing Adenoma Versus Idiopathic Hyperplasia The distinction between aldosterone-producing ade-noma(APA)andprimaryadrenalhyperplasia(PAH)iscrit-ical in evaluating a patient with confirmed primary aldoste-ronismandanadrenaltumor.These2entitiesaccountformore than 95% of all cases of primary aldosteronism (one-thirdAPAandtwo-thirdsPAH).ThedistinctioniscriticalbecauseAPAisoftensuccessfullymanagedsurgicallywithunilateral adrenalectomy (82 [EL 2]) (Fig. 3), whereasPAH is best managed medically with mineralocorticoidreceptorantagonists.Thisdistinction,however,iscloudedbyaphysiologicandpathologiccontinuum that includes

solitaryunilateralAPAs,bilateralordoubleAPAs,primaryunilateral hyperplasia, bilateral micronodular or mac-ronodularhyperplasia,andPAHinconjunctionwithoneormorenonfunctioningadrenal incidentalomas (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).PatientswithAPAareoftenyounger,havemoreseverehypertensionandhypokalemia, and demonstrate higher PAC and urinaryaldosterone levels (65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).PatientswithAPAoftenrespondbettertospironolactonethandothosewithPAH.Unfortunately,none of these observations is specific enough for subtype evaluation.

8.4. Imaging and Localization The ability to lateralize the source of aldosteroneexcess considerably facilitates the selection of patients forsurgicaltreatmentwhohavethegreatestlikelihoodforcure.AlthoughenhancedCTimagingreducesthenumberoffalse-negativestudies,itclearlyincreasesthenumberofstudieswithfalse-positiveresultsthatcouldleadtoeitherinappropriatewithholdingofsurgicalinterventionorsurgi-cal removalof thewronggland.Thischallengebecomesmore important with advancing age as the incidence ofadrenal incidentalomas increases. A young patient (less

Fig. 3. Algorithm for confirmation of primary aldosteronism. APA=aldoste-rone-producingadenoma;AVS=adrenalvenoussampling;CT=computedtomographic;PAH = primary adrenal hyperplasia. Modified with permission fromYoung(82 [EL 2]).

AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1) 1�

than 40 years) with primary aldosteronism who has an adrenaladenomalargerthan1cm(uniform,hypodense,noenhancementwithanintravenouslyadministeredcontrastagent)andamorphologicallynormalcontralateraladrenalglandneedsnofurtherimagingorevaluationandshouldbereferredforoperativeintervention.Olderpatients,patientswithbilateralmorphologicallyabnormalglands,or thosewithaunilateralmicroadenoma(ormicroadenomas)needtobeconsideredforbilateralAVStodistinguishAPAfromPAH and referred to a medical center familiar with thisprocedure. Patients too infirm for surgical management, those with a limited life expectancy, and those comfortable withmedical therapyutilizingmineralocorticoidreceptorblockersneednofurtherevaluation(65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).Patientsshoulddiscon-tinuetheuseofspironolactonefor6weeksandeplerenonefor 4 weeks before AVS. The success ofAVS is very much dependent on theoperator’s experience; thus, AVS should be relegated to medicalcenterswithabusyinterventionalradiologistded-icatedtothisparticularprocedure(66-68 [EL 3], 83 [EL 2]).Cannulationof thesmall rightadrenalveincanbeaformidable task. On the basis of a review of 47 reports, the success rate for cannulation of the right adrenal vein in 384 patients was 74% (69 [EL 4]). In more than 200 patients with primary aldosteronism treated (during 1990 to 2003) atamajorreferralcenter, thesuccessofbilateraladrenalvenous catheterization, as demonstrated by high adrenalveincortisol-to-systemiccortisollevels(undercontinuouscosyntropin infusion), was approximately 95% (83 [EL 2]).Associatedmorbidity,includingminorbleeding,hema-toma, dissection, and adrenal infarction, is exceedingly rare.Cortrosynstimulationalsoaugmentsthealdosterone/cortisol ratio in patients with APA. Aldosterone/cortisolratiosareusedtoaccountforthedilutionaleffectontheleftside due to mixing of blood from the inferior phrenic vein. Corrected aldosterone/cortisol ratios (aldosterone/cortisolratioofonesidetoaldosterone/cortisolratioof theotherside) of greater than 4 to 1 are indicative of a unilateral source of aldosterone excess, likely to be responsive to uni-lateraladrenalectomy.SomemedicalcentersperformAVSin all patients who have the diagnosis of primary aldo-steronism, whereas others advocate its selective use (forexample, AVS likely not needed in patients younger than age 40 years with a solitary adenoma on CT scan) (83 [EL 2], 84 [EL 3]).IfAVShadnotbeenusedandCTalonewasused to determine laterality in a cohort of 203 patients, 42 patients or 21% would have been inappropriately excluded ascandidatesforadrenalectomyand25%mighthavehadan unnecessary or inappropriate adrenalectomy (83 [EL 2], 85 [EL 4], 86 [EL 3].Thus,selectiveAVSshouldbeconsideredasanessentialstepindistinguishingAPAandprimaryunilateralhyperplasiafromPAHinthemajorityofthepatients(68 [EL 3], 84 [EL 3]).

8.5. Definitive Therapy Definitive therapy is essential for patients with pri-mary aldosteronism. Excess plasma aldosterone levels are deleterious,evenwhenhypertensionandhypokalemiaareadequatelycontrolled.Ifleftuntreatedorunblocked,aldo-sterone excess can lead to myocardial fibrosis, left ventricu-larhypertrophy,increasedmortalityfromcongestiveheartfailure,moreischemicevents,andincreasedvascularandclottingabnormalities(87-89 [EL 1], 90-95 [EL 2], 96-99 [EL 3]).Patientswhoaretoooldortooill,thosewithIHA,andthoserefusingsurgicalinterventionshouldbetreatedwithspironolactone(alongwithotherclassesofantihyper-tensiveagentsasneeded)orwitheplerenone(65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).Eplerenoneisarecentlyadded,corticosteroid-basedcompetitivemin-eralocorticoidreceptorantagonist.Unlikespironolactone,ithaslittleandrogenreceptorantagonistactivitythatoftenleads tountowardsideeffects inmen(gynecomastiaandimpotence)andmenstrualirregularitiesinwomen(71 [EL 2], 100 [EL 3], 101 [EL 3], 102 [EL 2], 103 [EL 1], 104 [EL 1]). Inpatientswithunequivocalevidenceofaunilateralsource of aldosterone excess and primary aldosteronism, unilateral laparoscopicadrenalectomy is the treatmentofchoice.Thelaparoscopicapproachiswellsuitedtopatientswithprimaryaldosteronismbecausethetumorsareusuallysmallandbenign(105-108 [EL 3], 109 [EL 4], 110 [EL 4]).Although cortex-sparing or partial adrenalectomy has been performed successfully in selected cases, this should beundertakenwithcautioninpatientswithaunilateralsourceof aldosterone excess. Pathologic specimens often demon-strateadditionalnodulesinthesameglandofpatientswitha dominant nodule. Theoretically, the dominant nodulemay be nonfunctioning; leaving the other nodules intactcouldresultinasurgicalfailure.Littlelong-termmorbidityhasbeennotedinpatientsundergoingacompleteunilateraladrenalectomyforprimaryaldosteronism. Physiologic outcomes are identical whether laparo-scopicoropenadrenalectomyisperformed(111 [EL 3]).Patients with a unilateral source of aldosterone excess, as determined by AVS, can expect a 100% cure of hypoka-lemia. More than 90% of patients will show substantial improvementinhypertension,asevidencedbyadecreasein the number of and dosing of antihypertensive medi-cations. Approximately 30% to 60% of patients will be abletodiscontinueallmedications;mostoften, theseareyoungerpatientswithashorterclinicalcourse(65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).Longdelaysindiagnosiscanresultinsecondaryrenalchanges,eventu-atinginsustainedbutimprovedhypertension.Inaddition,womenseemtofarebetterthanmen,andapositivefamilyhistoryofhypertensionseemstobeanegativepredictorforlong-termcontrolofhypertension(111 [EL 3]). An excel-lentresponsetospironolactoneisoftenpredictiveofasuc-

1� AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1)

cessfulresultfromadrenalectomy(67 [EL 3], 112-114 [EL 3]). Laparoscopicadrenalectomyhasadvantagesoveropenposterior and anterior adrenalectomy, including shorteroperativetime,brieferrecoveryperiod,lesspostoperativepain, less blood loss, and diminished overall long-termmorbidity(T12nerveinjury,hernias)(106 [EL 3], 108 [EL 3], 115-117 [EL 3]).If laparoscopictransperitonealadre-nalectomy cannot be accomplished because of an exten-sivepriorupperabdominalsurgicalprocedure,aposteriorendoscopicoropenapproachcanbeused(118 [EL 3]),theformer being preferable when expertise with this technique is available. Large aldosterone-secreting tumors (>6 cm)with noncontrast CT attenuation values >10 HU should be suspectedofbeingACCsandshouldbemanagedaccord-inglywithanopensurgicalapproach.

8.6. Preparation for Surgical Procedure and Postoperative Care Inpreparationforsurgicaltreatment,mostpatientsaregivenamineralocorticoidreceptorantagonist,alongwithothernecessaryantihypertensiveandcardiacmedications.Potassiumstoresarerepletedcautiouslyinpatientsreceiv-ingmineralocorticoidreceptorantagonists.Postoperatively,potassiumchloridereplacementiscontinueduntilnormoka-lemia can be maintained. Mineralocorticoid receptor antag-onistsarestopped,andantihypertensiveagentsarewithheldunlessbloodpressureremainselevated.Antihypertensivemedicationsareaddedbackorweanedinaccordancewithbloodpressuremeasurements.Normotensionwithoutuseofanymedicationsmaytakeweekstomonthstoachieveormaynotbepossible(65 [EL 4], 71 [EL 2], 72 [EL 2], 75 [EL 4], 76 [EL 4]).Duringtheperioperativeperiod,β-adrenergicblockingagentsshouldnotbeabruptlydiscon-tinued,andtheymaynecessitatecontinueduseinpatientsreceivinglong-termtherapyforischemicheartdisease.

9. ADRENOCORTICAL CARCINOMA

9.1. Overview PatientswithACC,araremalignantlesion,haveapoorprognosis.Twodeterminantsoflong-termsurvivalarethetumor stage at presentation and curative resection by anexperienced surgeon (119 [EL 3]).ThegoalofanadrenalincidentalomascreeningprotocolistoidentifyallpatientswithACC(4 [EL 4], 6 [EL 4], 40 [EL 4]).Nevertheless,definitive preoperative diagnosis of ACC is impossible by meansofbiochemicalorcytologictesting.BecausetheriskofACCisdeterminedbytheradiographicphenotypeofalesion,thestrategyistooperateonallpatientsconsideredatriskonthebasisoftheradiographicappearanceoftheincidentaloma.Inapooledanalysisfrom26internationalstudies,ACCconstituted<5%ofalladrenalincidentalomas (120 [EL 3]).Clearly,however,ACCprevalencedependson the size of the tumor, accounting for 2% of lesions ≤4

cm, 6% of lesions from 4.1 to 6 cm, and 25% of lesions largerthan6cm(6 [EL 4]). Two-thirdsof allACCs arehormonally active (121-123 [EL 3])andtendtomanifestwithhypercortisolismandvirilization (and, rarely,aldosteronismand feminization).Ingeneral,however,theACCsmanifestingasradiographicincidentalomasareclinicallynonfunctioningtumors. An incidentaloma with >10 HU attenuation on non-contrastCTisconcerningforanACC,mostofwhichhavean attenuation >30 HU (14 [EL 3]).Thedifferentialdiag-nosis essentially includes pheochromocytoma, metastaticlesion, lipid-poor adenoma, orACC. Biochemical evalu-ation will exclude a pheochromocytoma and may provide cluestothepresenceofahormonallyactiveACC,althoughtheselesionsaretypicallyobviousclinically.Thedistinc-tionbetweenametastatic lesionandaprimaryACCcanbe difficult, although radiographic features can occasion-ally be of help in distinguishing between the 2. Most com-monly,metastaticdiseasemanifestsinpatientswithapriorhistory of a malignant tumor during evaluation (often inconsultation with a patient’s oncologist) for a recurrentprimary lesion or evidence of other metastatic disease.Judicioususeofabiopsymaybehelpfulafterthediagno-sis of a pheochromocytoma has been excluded; however, a CT-guided fine-needle aspiration (FNA) may not distin-guishACCfromabenignadenoma.Ifmetastaticdiseaseis unlikely, anopen adrenalectomy for a suspectedACCshouldbeperformed(124 [EL 3]).

9.2. Clinical Evaluation A paucity of clinical symptoms is frequently a fea-tureofahormonally inactive,albeit large,ACCinciden-tally found radiographically. Some causes of ACC maymanifest with flank pain, vague abdominal discomfort, and occasionallyfeverduetohemorrhagewithinthetumor.Incontrast,hormonallyactivelesionsmanifestwithdramaticand rapidly progressive symptoms of hypercortisolism,virilization, or, less frequently, feminization or aldoste-ronism. Typically, these lesions are suspected clinically.The initial manifestations of hormonally inactive tumorsmaybeabdominalpressureorfullnessattributabletomasscompressionofadjacentstructures.

9.3. Biochemical Evaluation Detailed hormonal evaluation is critical before sur-gical resection inapatient suspectedofhavinganACC.Eveninpatientswithoutclinicalstigmas,highcirculatinglevels of steroid precursors may be found. Patients withcortisol-producingACCareatriskofpostoperativeadrenalinsufficiency attributable to suppression of the HPA axis andwillrequirepostoperativecorticosteroidreplacement.Moreover, any hormonal markers identified before resec-tionwillserveastumormarkersduringpostoperativesur-veillance.PatientsneedtoundergobiochemicalevaluationforCushingsyndromeandaldosteronism(ifhypertensive),


as we already described. Clinicians can test for sex steroids andsteroidprecursors,includingandrostenedione,testos-terone,dehydroepiandrosteronesulfate,and17β-estradiol(inpostmenopausalwomenandmenonly)(119 [EL 3]).9.4. Radiographic Evaluation ThesizeofthelesioncanbeamajorpredictorofanACC in an incidentaloma with >10 HU attenuation on non-contrast CT. Multiple studies have addressed this relation-ship(125 [EL 3]).Inarecentstudyof81patients,accord-ingtoareceiveroperatingcharacteristiccurveanalysis,thecutoffvalueoftumorsizetodistinguishbetweenamalig-nant tumor and a benign lesion was 4.75 cm, with a sen-sitivity of 90% and a specificity of 58% (16 [EL 3]).TheNationalItalianStudyGrouponAdrenalTumors(125 [EL 3]) determined that the cutoff of 4 cm was associated with a 93% sensitivity and a specificity of 24%. In addition to HU,otherfeaturesthatcauseconcernforamalignantlesionincludeirregularshapeandaninhomogeneouspatternofenhancementduetocentralareasofnecrosis.Invasionintosurrounding tissues, especially the inferior vena cava, orthrombosismakesthepresenceofACChighlylikely.Forintraoperativeplanning,amagneticresonanceangiogrammaybeuseful.

9.5. Operative Management Open adrenalectomy by an experienced surgeon is the procedure of choice. Patients with ACC shouldundergo en bloc resection of the involved adrenal glandandsurroundingtissues(kidney,liver,inferiorvenacava).Lymphadenectomy is required as well. Leaving the cap-suleintactduringresectionreducesthepossibilityoflocalrecurrence(119 [EL 3]). Several published reports of laparoscopic adrenalec-tomieshaveincludedACC;mostweresmallerlesionsthatwereunrecognizedasACCpreoperatively.Increasedriskof early local recurrence, peritoneal dissemination, andport entry site seeding has been observed (126-129 [EL 3]).Onthebasisofthisevidence,itisprudenttoconverttoopenresectionifACCissuspectedintraoperatively. Adjuvantmitotanetreatmentmaybeconsideredpost-operatively in selected patients who have undergone acompleteresectionoftheirACCandhavepoorprognosticfeatures(130 [EL 4]).

10. METASTATIC DISEASE

10.1. Overview Metastatic disease to the adrenal glands is rarely found inpatientswithout anyhistoryof aknownmalig-nant lesion.Twopooledanalysesof international studiesreporteda2.1%to2.5%prevalenceofmetastaticlesionsamong incidentalomas (4 [EL 4], 120 [EL 3]). Even inpatients who are undergoing assessment for a suspectedmalignant tumor, an adrenal metastatic lesion is rarely

found at diagnosis. In a series of 1,639 patients suspected of havinganoccultmalignantlesion,anadrenalmasswastheinitialmanifestationinonly5.8%ofcases(131 [EL 3]). Lung,breast,stomach,andkidneycancersandmela-nomas and lymphomas most commonly metastasize totheadrenalglands(132 [EL 2]).Themajorityofadrenallesions found in a patient with a history of any of thesemalignantconditionswillprovetobeametastaticgrowth.Pheochromocytomas shouldbe ruledoutwithbiochemi-caltestingineachpatient(133 [EL 3]).AnothercauseofadrenallesionsisACC;otherprimaryadrenaltumorsarelessfrequentinthisgroup.IntheseriesreportedbyLenertetal(133 [EL 3]), only 3 patients (4%) had an ACC. Theprocessofdistinctionbetweenametastaticlesionandaprimaryadrenaltumorisaidedbytheknowledgeofa past cancer type in a specific patient. Targeted evalua-tionforlocoregionalrecurrenceandothermetastaticsitesshouldbeplanned in consultationwith anoncologist. Inaddition to cancer-specific tests, this investigation typically includescontrast-enhancedCTofthechest,abdomen,andpelvis. Fludeoxyglucose (FDG)-positron emission tomog-raphy(PET)/CTisfrequentlybeingusedinrestagingpro-tocolsforFDG-avidmalignanttumorsandcanbehelpfulin documenting other extra-adrenal metastatic lesions. If a definitive diagnosis is needed for oncologic treatment plan-ning, CT-guided FNA can be performed—but only afterthe diagnosis of pheochromocytoma has been excluded.

10.2. Clinical Evaluation Thehistoryshouldfocusonelicitingapersonalhistoryof prior malignant lesions, weight loss, unexplained fevers, adherencetoanage-appropriatecancerscreeningprogram,familyhistoryofmalignantconditions,andsmokinghis-tory. Physical examination may reveal lymphadenopathy ormaysuggestthepresenceofalungmass,breastmass,or skin lesion suspicious for melanoma as well as othercancer-specific findings.

10.3. Radiographic Evaluation Documentationofradiologiccriteriaforanadenomacan exclude the presence of a malignant tumor. Metastatic lesionsareheterogeneouswith irregularmarginsandarebilateral in 10% to 15% of cases (131 [EL 3], 132 [EL 2], 134 [EL 3]).Thesizeofametastaticlesionvarieswidelyfrom 0.8 to 20 cm (131 [EL 3], 132 [EL 2], 135 [EL 3]).Othermetastaticdiseaseorlymphadenopathyispresentinup toone-thirdofcases (133 [EL 3]).The roleofFDG-PETinmetastaticdiseaseisinevolution.Itdoesnotdistin-guishbetweenanadrenalmetastaticgrowthandanACC,bothofwhichareFDG-avidlesions.Itdoes,however,havea role in detecting extra-adrenal metastatic disease both in patientswithACCandinthosewithahistoryofanFDG-avid malignant tumor (for example, lung or breast cancer) (135 [EL 3]).


10.4. Further Preoperative Evaluation Allpatientswithbilateraladrenalinvolvementshouldundergo evaluation for adrenal insufficiency (4 [EL 4], 132 [EL 2]). Patents suspected of having a metastatic lesionfromapreviously treated cancer shouldundergo evalua-tion,withtheassistanceofanoncologist,withtumor-spe-cific markers and global imaging (contrast-enhanced CT of the chest, abdomen, and pelvis, site-specific MRI or FDG-PET/CT[orboth],andbonescanning)tosearchforothersitesofmetastaticinvolvement. IfmetastaticdiseaseislikelyandACCisunlikelyonthe basis of biochemical, clinical, and radiographic find-ings, FNA biopsy can be used to confirm the diagnosis of metastatic disease. This technique allows distinctionbetweenadrenalandnonadrenaltissue(metastaticgrowth,infection).TherisksofFNAarewelldescribedandincludeadrenalhematomaorabscess,abdominalpain,hematuria,pancreatitis, pneumothorax, and tumor recurrence in the biopsytrack(40 EL 4]).Thepatientshouldundergobio-chemicalevaluationforpheochromocytomabeforebiopsy,inlightoftheriskoffatalhypertensivecrisisduringFNA(136 [EL 3], 137 [EL 3]).Cross-sectionalimaging2weeksbeforetheplannedsurgicalprocedureshouldbedoneforsuspectedmetastaticlesions,inasmuchasthesecangrowrapidly. If there are signs of locoregional invasion ordevelopmentofdiseaseatothersites,surgicalinterventionshouldbecanceled.

10.5. Operative Management Resectionofanadrenalmetastaticlesioncanbeper-formedforsymptomaticpalliation.Surgicalresectioncanimprove disease-free survival in a very select group ofpatients with good control of their extra-adrenal disease andagoodperformancestatus(132 [EL 2], 133 [EL 3]).Unfortunately, most patients with adrenal metastatic dis-easehaveapooroverallprognosis,withameandurationofsurvivalof3months(132 [EL 2]).

DISCLOSURE

Cochairpersons/Primary Writers Dr. Martha A. Zeigerreportsthatshedoesnothaveany relevant financial relationships with any commercial interests. Dr. Geoffrey B. Thompson reports that he does nothave any relevant financial relationships with any commer-cialinterests. Dr. Quan-Yang Duhreportsthathehasreceivedadvi-soryboardhonoriafromCovidien. Dr. Amir H. Hamrahianreportsthathedoesnothaveany relevant financial relationships with any commercial interests.

Primary Writers Dr. Peter AngelosreportsthathehasreceivedfacultyhonorariafromEthiconEndo-Surgery,Inc. Dr. Dina Elaraj reports that she does not have anyrelevant financial relationships with any commercial interests. Dr. Elliot Fishman reports that he has receivedresearchgrant support fromGEHealthcare andSiemensAG. Dr. Julia Kharlip reports that she does not haveany relevant financial relationships with any commercial interests.

American Association of Clinical Endocrinologists Reviewers Dr. Jeffrey R. Garber reports that hedoesnothaveany relevant financial relationships with any commercial interests. Dr. Jeffrey I. Mechanickreportsthathedoesnothaveany relevant financial relationships with any commercial interests.

American Association of Endocrine Surgeons Reviewers Dr. Michael J. Demeurereportsthathedoesnothaveany relevant financial relationships with any commercial interests. Dr. William B. Inabnet reports that hehas receivedresearchgrantsupportfromCovidien.

REFERENCES

Note: All reference sources are followed by an evidence level [EL] rating of 1, 2, 3, or 4. The strongest evidence lev-els (EL 1 and EL 2) appear in red for easier recognition.

1. Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered adrenal masses. Endocr Rev.1995;16:460-484. [EL 3]

2. Gajraj H, young AE.Adrenal incidentaloma.Br J Surg.1993;80:422-426. [EL 3]

3. Libè R, Dall’Asta C, Barbetta L, Baccarelli A, Beck-Peccoz P, Ambrosi B. Long-term follow-up study ofpatients with adrenal incidentalomas. Eur J Endocrinol.2002;147:489-494. [EL 2]

4. young WF Jr. Management approaches to adrenal inci-dentalomas: a view from Rochester, Minnesota. Endocrinol Metab Clin North Am. 2000;29:159-185, x. [EL 4]

5. Grumbach MM, Biller BM, Braunstein GD, et al.Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med. 2003;138:424-429. [EL 4]

6. NIHstate-of-the-sciencestatementonmanagementoftheclinicallyinapparentadrenalmass(“incidentaloma”).NIH Consens State Sci Statements. 2002;19:1-25. [EL 4]

AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1) 1�

7. Mechanick JI, Bergman DA, Braithwaite SS, Palumbo PJ (AACE Ad Hoc Task Force for Standardized Production of Clinical Practice Guidelines).AmericanAssociationofClinicalEndocrinologistsprotocolforstan-dardizedproductionofclinicalpracticeguidelines.Endocr Pract. 2004;10:353-361. [EL 4]

8. Caoili EM, Korobkin M, Francis IR, et al. Adrenalmasses: characterization with combined unenhanced anddelayedenhancedCT.Radiology. 2002;222:629-633. [EL 2]

9. Mantero F, Terzolo M, Arnaldi G, et al (Study Group on Adrenal Tumors of the Italian Society of Endocrinology). A survey on adrenal incidentaloma inItaly.J Clin Endocrinol Metab. 2000;85:637-644. [EL 2]

10. young WF Jr.Primaryaldosteronism:acommonandcur-able formofhypertension.Cardiol Rev. 1999;7:207-214. [EL 4]

11. Lenders JW, Pacak K, Walther MM, et al.Biochemicaldiagnosisofpheochromocytoma:whichtestisbest?JAMA.2002;287:1427-1434. [EL 4]

12. Sawka AM, Jaeschke R, Singh RJ, young WF Jr.Acom-parisonofbiochemicaltestsforpheochromocytoma:mea-surementoffractionatedplasmametanephrinescomparedwith the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab. 2003;88:553-558.[EL 3]

13. Korobkin M, Brodeur FJ, yutzy GG, et al.DifferentiationofadrenaladenomasfromnonadenomasusingCTattenua-tionvalues.AJR Am J Roentgenol. 1996;166:531-536. [EL 3]

14. Hamrahian AH, Ioachimescu AG, Remer EM, et al.Clinicalutilityofnoncontrastcomputedtomographyatten-uation value (Hounsfield units) to differentiate adrenal ade-nomas/hyperplasias fromnonadenomas:ClevelandClinicexperience. J Clin Endocrinol Metab. 2005;90:871-877. [EL 3]

15. Barry MK, van Heerden JA, Farley DR, Grant CS, Thompson GB, Ilstrup DM. Can adrenal incidentalo-masbe safelyobserved [withdiscussion]?World J Surg.1998;22:599-604. [EL 3]

16. Kim Hy, Kim SG, Lee KW, et al. Clinical study ofadrenal incidentaloma in Korea. Korean J Intern Med.2005;20:303-309. [EL 3]

17. Barzon L, Scaroni C, Sonino N, Fallo F, Paoletta A, Boscaro M.Riskfactorsandlong-termfollow-upofadre-nalincidentalomas.J Clin Endocrinol Metab. 1999;84:520-526.[EL 2]

18. Höfle G, Gasser RW, Lhotta K, Janetschek G, Kreczy A, Finkenstedt G.Adrenocortical carcinoma evolving afterdiagnosisofpreclinicalCushing’ssyndromeinanadrenalincidentaloma:acasereport.Horm Res. 1998;50:237-242. [EL 3]

19. Ghose RP, Hall PM, Bravo EL. Medical management of aldosterone-producing adenomas. Ann Intern Med.1999;131:105-108. [EL 3]

20. Sirén J, Tervahartiala P, Sivula A, Haapiainen R.Naturalcourseofadrenal incidentalomas:seven-yearfol-low-upstudy.World J Surg. 2000;24:579-582. [EL 3]

21. Linos DA. Management approaches to adrenal incidentalo-mas(adrenalomas):aviewfromAthens,Greece.Endocrinol Metab Clin North Am. 2000;29:141-157. [EL 4]

22. Brunt LM, Moley JF. Adrenal incidentaloma. World J Surg. 2001;25:905-913. [EL 4]

23. Sippel RS, Chen H. Subclinical Cushing’s syndrome inadrenalincidentalomas.Surg Clin North Am. 2004;84:875-885.[EL 4]

24. Findling JW, Raff H. Newer diagnostic techniques andproblems in Cushing’s disease. Endocrinol Metab Clin North Am. 1999;28:191-210. [EL 4]

25. Findling JW, Raff H.DiagnosisanddifferentialdiagnosisofCushing’ssyndrome.Endocrinol Metab Clin North Am.2001;30:729-747. [EL 4]

26. Findling JW, Raff H. Cushing’s syndrome: importantissues in diagnosis and management. J Clin Endocrinol Metab. 2006;91:3746-3753. [EL 3]

27. Arnaldi G, Angeli A, Atkinson AB, et al.Diagnosis andcomplications of Cushing’s syndrome: a consensus state-ment.J Clin Endocrinol Metab. 2003;88:5593-5602. [EL 4]

28. Turpeinen U, Markkanen H, Välimaki M, Stenman UH.DeterminationofurinaryfreecortisolbyHPLC.Clin Chem. 1997;43:1386-1391. [EL 3]

29. Nieman LK, Biller BM, Findling JW, et al.ThediagnosisofCushing’ssyndrome:anEndocrineSocietyclinicalprac-tice guideline. J Clin Endocrinol Metab. 2008;93:1526-1540. [EL 4]

30. Kazama I, Komatsu y, Ohiwa T, Sanayama K, Nagata M. Delayed adrenal insufficiency long after unilateral adrenalectomy:prolongedglucocorticoid therapyreducedreservedsecretorycapacityofcortisol.Int J Urol. 2005;12: 574-577. [EL 3]

31. Nieman LK, Ilias I.EvaluationandtreatmentofCushing’ssyndrome.Am J Med. 2005;118:1340-1346. [EL 4]

32. Doherty GM, Nieman LK, Cutler GB Jr, Chrousos GP, Norton JA. Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing’s syndrome. Surgery.1990;108:1085-1090. [EL 2]

33. Chiodini I, Losa M, Pavone G, Trischittal V, Scillitani A.PregnancyinCushing’sdiseaseshortlyaftertreatmentbygamma-knife radiosurgery.J Endocrinol Invest. 2004;27: 954-956. [EL 3]

34. Terzolo M, Pia A, Alì A, et al.Adrenalincidentaloma:anewcauseofthemetabolicsyndrome?J Clin Endocrinol Metab. 2002;87:998-1003. [EL 3]

35. Tauchmanovà L, Rossi R, Biondi B, et al.Patientswithsubclinical Cushing’s syndrome due to adrenal adenomahave increased cardiovascular risk. J Clin Endocrinol Metab. 2002;87:4872-4878. [EL 3]

36. Garrapa GG, Pantanetti P, Arnaldi G, Mantero F, Faloia E. Body composition and metabolic features in womenwithadrenalincidentalomaorCushing’ssyndrome.J Clin Endocrinol Metab. 2001;86:5301-5306. [EL 3]

37. Reincke M.SubclinicalCushing’ssyndrome.Endocrinol Metab Clin North Am. 2000;29:43-56. [EL 4]

38. Valli N, Catargi B, Ronci N, et al.Biochemicalscreeningforsubclinicalcortisol-secretingadenomasamongstadre-nal incidentalomas.Eur J Endocrinol. 2001;144:401-408. [EL 3]

39. Barzon L, Fallo F, Sonino N, Boscaro M. Overnightdexamethasone suppression of cortisol is associated with radiocholesteroluptakepatternsinadrenalincidentalomas.Eur J Endocrinol. 2001;145:223-224. [EL 3]

40. young WF Jr. Clinical practice: the incidentally discov-eredadrenalmass.N Engl J Med. 2007;356:601-610. [EL 4]

41. Huiras CM, Pehling GB, Caplan RH. Adrenal insuffi-ciencyafteroperativeremovalofapparentlynonfunction-ingadrenaladenomas.JAMA. 1989;261:894-898. [EL 3]

42. Krikorian A, Abdelmannan D, Selman WR, Arafah BM.Cushingdisease:useofperioperativeserumcortisolmeasurementsinearlydeterminationofsuccessfollowingpituitarysurgery.Neurosurg Focus. 2007;23:E6. [EL 4]


43. Esposito F, Dusick JR, Cohan P, et al.Clinical review:early morning cortisol levels as a predictor of remissionaftertranssphenoidalsurgeryforCushing’sdisease.J Clin Endocrinol Metab. 2006;91:7-13. [EL 2]

44. Mansmann G, Lau J, Balk E, Rothberg M, Miyachi y, Bornstein SR. The clinically inapparent adrenalmass:update indiagnosis andmanagement.Endocr Rev.2004;25:309-340. [EL 4]

45. Werbel SS, Ober KP. Pheochromocytoma: update ondiagnosis,localization,andmanagement.Med Clin North Am. 1995;79:131-153. [EL 4]

46. Bryant J, Farmer J, Kessler LJ, Townsend RR, Nathanson KL. Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst. 2003;95:1196-1204. [EL 4]

47. Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al.Clinical presentation and penetrance of pheochromocy-toma/paragangliomasyndromes.J Clin Endocrinol Metab.2006; 91:827-836. [EL 2]

48. Gutmann DH, Aylsworth A, Carey JC, et al.Thediag-nostic evaluation and multidisciplinary management ofneurofibromatosis 1 and neurofibromatosis 2. JAMA.1997;278:51-57. [EL 2]

49. Quint LE, Glazer GM, Francis IR, Shapiro B, Chenevert TL. Pheochromocytoma and paraganglioma: comparisonof MR imaging with CT and I-131 MIBG scintigraphy. Radiology. 1987;165:89-93. [EL 3]

50. Velchik MG, Alavi A, Kressel Hy, Engelman K.Localization of pheochromocytoma: MIBG [correction of MIGB], CT, and MRI correlation. J Nucl Med. 1989;30:328-336.[EL 3]

51. Francis IR, Gross MD, Shapiro B, Korobkin M, Quint LE.Integratedimagingofadrenaldisease[publishedcor-rection appears in Radiology. 1992;185:286]. Radiology.1992;184:1-13. [EL 4]

52. Ilias I, Pacak K. Current approaches and recommendedalgorithmforthediagnosticlocalizationofpheochromocy-toma.J Clin Endocrinol Metab. 2004;89:479-491. [EL 4]

53. Kebebew E, Duh Qy.Benignandmalignantpheochromo-cytoma: diagnosis, treatment, and follow-up. Surg Oncol Clin N Am. 1998;7:765-789. [EL 4]

54. Gimenez-Roqueplo AP, Favier J, Rustin P, et al (COMETE Network). Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochro-mocytomas.Cancer Res. 2003;63:5615-5621. [EL 3]

55. Pacak K. Preoperative management of the pheochromo-cytoma patient. J Clin Endocrinol Metab. 2007;92:4069-4079. [EL 4]

56. Perry RR, Keiser HR, Norton JA, et al.Surgicalman-agementofpheochromocytomawiththeuseofmetyrosine.Ann Surg. 1990;212:621-628. [EL 3]

57. Steinsapir J, Carr AA, Prisant LM, Bransome ED Jr.Metyrosine and pheochromocytoma. Arch Intern Med.1997;157:901-906. [EL 3]

58. Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, featuresat presentation, and risk of recurrence in patients withpheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab. 2005;90:2110-2116. [EL 3]

59. Obara T, Ito y, Okamoto T, et al.Riskfactorsassociatedwithpostoperativepersistenthypertensioninpatientswithprimary aldosteronism. Surgery. 1992;112:987-993. [EL 3]

60. Mulatero P, Stowasser M, Loh KC, et al. Increaseddiagnosis of primary aldosteronism, including surgically

correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045-1050. [EL 3]

61. Huang yy, Hsu BR, Tsai JS. Paralytic myopathy—aleadingclinicalpresentationforprimaryaldosteronisminTaiwan. J Clin Endocrinol Metab. 1996;81:4038-4041. [EL 3]

62. Lo Cy, Tam PC, Kung AW, Lam KS, Wong J.Primaryaldosteronism: results of surgical treatment. Ann Surg.1996;224:125-130. [EL 3]

63. Ganguly A, Zager PG, Luetscher JA.Primaryaldosteron-ismduetounilateraladrenalhyperplasia.J Clin Endocrinol Metab. 1980;51:1190-1194. [EL 3]

64. Irony I, Kater CE, Biglieri EG, Shackleton CH.Correctable subsets of primary aldosteronism: primaryadrenalhyperplasia and renin responsive adenoma.Am J Hypertens. 1990;3:576-582. [EL 3]

65. young WF Jr. Minireview: primary aldosteronism—chang-ing concepts in diagnosis and treatment. Endocrinology.2003;144:2208-2213. [EL 4]

66. Doppman JL, Gill JR Jr.Hyperaldosteronism:samplingtheadrenalveins.Radiology. 1996;198:309-312. [EL 3]

67. Rossi GP, Sacchetto A, Chiesura-Corona M, et al.Identification of the etiology of primary aldosteronism with adrenal vein sampling in patients with equivocalcomputed tomography and magnetic resonance findings: results in 104 consecutive cases. J Clin Endocrinol Metab.2001;86:1083-1090. [EL 3]

68. young WF Jr, Stanson AW, Grant CS, Thompson GB, van Heerden JA.Primaryaldosteronism:adrenalvenoussampling [with discussion]. Surgery. 1996;120:913-920. [EL 3]

69. young WF Jr, Klee GG. Primary aldosteronism: diag-nostic evaluation. Endocrinol Metab Clin North Am.1988;17:367-395. [EL 4]

70. Hiramatsu K, yamada T, yukimura y, et al.Ascreeningtesttoidentifyaldosterone-producingadenomabymeasur-ingplasmareninactivity:resultsinhypertensivepatients.Arch Intern Med. 1981;141:1589-1593. [EL 2]

71. Lim PO, young WF, MacDonald TM.A review of themedicaltreatmentofprimaryaldosteronism.J Hypertens.2001;19:353-361. [EL 2]

72. Montori VM, young WF Jr.Useofplasmaaldosteroneconcentration-to-plasmareninactivityratioasascreeningtestforprimaryaldosteronism:asystematicreviewoftheliterature.Endocrinol Metab Clin North Am. 2002;31:619-632, xi. [EL 2]

73. Weinberger MH, Fineberg NS.Thediagnosisofprimaryaldosteronismandseparationoftwomajorsubtypes.Arch Intern Med. 1993;153:2125-2129. [EL 2]

74. Hamlet SM, Tunny TJ, Woodland E, Gordon RD. Isaldosterone/reninratiousefultoscreenahypertensivepop-ulation for primary aldosteronism? Clin Exp Pharmacol Physiol. 1985;12:249-252. [EL 4]

75. young WF Jr.Primaryaldosteronism—treatmentoptions.Growth Horm IGF Res. 2003;13(suppl A):S102-S108. [EL 4]

76. young WF Jr.Primaryaldosteronism:managementissues.Ann N Y Acad Sci. 2002;970:61-76. [EL 4]

77. young WF Jr, Hogan MJ, Klee GG, Grant CS, van Heerden JA.Primaryaldosteronism:diagnosisandtreat-ment.Mayo Clin Proc. 1990;65:96-110. [EL 2]

78. Funder JW, Carey RM, Fardella C, et al (Endocrine Society). Case detection, diagnosis, and treatment ofpatientswithprimaryaldosteronism:anEndocrineSocietyclinicalpracticeguideline.J Clin Endocrinol Metab. 2008; 93:3266-3281. [EL 4]


79. Mosso L, Carvajal C, González A, et al.Primaryaldoste-ronism and hypertensive disease. Hypertension. 2003;42: 161-165.[EL 2]

80. Stowasser M, Gordon RD.Primaryaldosteronism—care-ful investigation is essential and rewarding. Mol Cell Endocrinol. 2004;217:33-39. [EL 2]

81. Stowasser M, Gordon RD, Tunny TJ, Klemm SA, Finn WL, Krek AL. Familial hyperaldosteronism type II: five familieswithanewvarietyofprimaryaldosteronism.Clin Exp Pharmacol Physiol. 1992;19:319-322. [EL 3]

82. young WF Jr.Adrenal-dependenthypertension.Probl Gen Surg. 2003;20:68-80. [EL 2]

83. young WF, Stanson AW, Thompson GB, Grant CS, Farley DR, van Heerden JA.Roleforadrenalvenoussam-pling in primary aldosteronism. Surgery. 2004;136:1227-1235.[EL 2]

84. Tan yy, Ogilvie JB, Triponez F, et al.Selectiveuseofadrenal venous sampling in the lateralization of aldoste-rone-producingadenomas[withdiscussion].World J Surg.2006;30:879-887. [EL 3]

85. Gordon RD. Mineralocorticoid hypertension. Lancet.1994;344:240-243. [EL 4]

86. Nwariaku FE, Miller BS, Auchus R, et al.Primaryhyper-aldosteronism:effectofadrenalveinsamplingonsurgicaloutcome[withdiscussion].Arch Surg. 2006;141:497-503. [EL 3]

87. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium pro-file with the risk of myocardial infarction in patients with hypertension.N Engl J Med. 1991;324:1098-1104. [EL 1]

88. Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT.Remodeling of the rat right and left ventricles in experi-mental hypertension. Circ Res. 1990;67:1355-1364. [EL 1]

89. Pitt B, Zannad F, Remme WJ, et al (Randomized Aldactone Evaluation Study Investigators).Theeffectofspironolactoneonmorbidityandmortalityinpatientswithsevereheartfailure.N Engl J Med. 1999;341:709-717. [EL 1]

90. Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of therenin-angiotensinsystemonplasmaPAI-1.Hypertension.1998;32:965-971. [EL 2]

91. Brown NJ, Kim KS, Chen yQ, et al.SynergisticeffectofadrenalsteroidsandangiotensinIIonplasminogenacti-vator inhibitor-1 production. J Clin Endocrinol Metab.2000;85:336-344. [EL 2]

92. Kerins DM, Hao Q, Vaughan DE.Angiotensininductionof PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest. 1995;96:2515-2520. [EL 2]

93. Martinez DV, Rocha R, Matsumura M, et al. Cardiacdamage prevention by eplerenone: comparison with lowsodiumdietorpotassiumloading.Hypertension. 2002;39(2 pt 2):614-618. [EL 2]

94. Rocha R, Rudolph AE, Frierdich GE, et al.Aldosteroneinduces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol. 2002;283:H1802-H1810. [EL 2]

95. Vaughan DE, Lazos SA, Tong K.Angiotensin II regu-lates the expression of plasminogen activator inhibitor-1 inculturedendothelial cells: apotential linkbetween therenin-angiotensin system and thrombosis. J Clin Invest.1995;95:995-1001. [EL 2]

96. Rocha R, Funder JW. The pathophysiology of aldo-sterone in the cardiovascular system. Ann N Y Acad Sci.2002;970:89-100. [EL 3]

97. Rocha R, Williams GH. Rationale for the use of aldo-sterone antagonists in congestive heart failure. Drugs.2002;62:723-731. [EL 3]

98. Sawathiparnich P, Kumar S, Vaughan DE, Brown NJ.Spironolactoneabolishestherelationshipbetweenaldoste-rone and plasminogen activator inhibitor-1 in humans. J Clin Endocrinol Metab. 2002;87:448-452. [EL 3]

99. Stier CT Jr, Chander PN, Rocha R. Aldosterone as amediatorincardiovascularinjury.Cardiol Rev. 2002;10:97-107. [EL 3]

100. de Gasparo M, Joss U, Ramjoué HP, et al. Three newepoxy-spirolactone derivatives: characterization in vivo and invitro.J Pharmacol Exp Ther. 1987;240:650-656. [EL 3]

101. Zillich AJ, Carter BL. Eplerenone—a novel selectivealdosterone blocker. Ann Pharmacother. 2002;36:1567-1576.[EL 3]

102. Jeunemaitre x, Chatellier G, Kreft-Jais C, et al. Efficacy and toleranceofspironolactone inessentialhypertension.Am J Cardiol. 1987;60:820-825. [EL 2]

103. Krum H, Nolly H, Workman D, et al. Efficacy of eplere-noneaddedtorenin-angiotensinblockadeinhypertensivepatients.Hypertension. 2002;40:117-123. [EL 1]

104. Weinberger MH, Roniker B, Krause SL, Weiss RJ.Eplerenone, a selective aldosterone blocker, in mild-to-moderatehypertension.Am J Hypertens. 2002;15:709-716. [EL 1]

105. Gagner M.Laparoscopicadrenalectomy.Surg Clin North Am. 1996;76:523-537. [EL 3]

106. Gagner M, Lacroix A, Prinz RA, et al. Early experience with laparoscopic approach for adrenalectomy [with dis-cussion].Surgery. 1993;114:1120-1125. [EL 3]

107. Kebebew E, Siperstein AE, Duh Qy.Laparoscopicadre-nalectomy:theoptimalsurgicalapproach.J Laparoendosc Adv Surg Tech A. 2001;11:409-413. [EL 3]

108. Marescaux J, Mutter D, Wheeler MH. Laparoscopicright and left adrenalectomies: surgical procedures. Surg Endosc. 1996;10:912-915. [EL 3]

109. Higashihara E, Tanaka y, Horie S, et al.Laparoscopicadrenalectomy: the initial3cases.J Urol. 1993;149:973-976. [EL 4]

110. Suzuki K, Kageyama S, Ueda D, et al. Laparoscopicadrenalectomy: clinical experience with 12 cases. J Urol.1993;150:1099-1102. [EL 4]

111. Sawka AM, young WF, Thompson GB, et al. Primaryaldosteronism: factors associated with normalization ofbloodpressureaftersurgery.Ann Intern Med. 2001;135:258-261.[EL 3]

112. Celen O, O’Brien MJ, Melby JC, Beazley RM.Factorsinfluencing outcome of surgery for primary aldosteronism. Arch Surg. 1996;131:646-650. [EL 3]

113. Ferriss JB, Brown JJ, Fraser R, et al.Resultsofadrenalsurgery in patients with hypertension, aldosterone excess, andlowplasmareninconcentration.Br Med J. 1975;1:135-138.[EL 3]

114. Hunt TK, Schambelan M, Biglieri EG. Selection ofpatientsandoperativeapproachinprimaryaldosteronism.Ann Surg. 1975;182:353-361. [EL 3]

115. Linos DA, Stylopoulos N, Boukis M, Souvatzoglou A, Raptis S, Papadimitriou J.Anterior,posterior,orlaparo-scopicapproachforthemanagementofadrenaldiseases?Am J Surg. 1997;173:120-125. [EL 3]


116. Prinz RA.Acomparisonoflaparoscopicandopenadrenal-ectomies[withdiscussion].Arch Surg. 1995;130:489-494. [EL 3]

117. Thompson GB, Grant CS, van Heerden JA, et al.Laparoscopicversusopenposterioradrenalectomy:acase-control study of 100 patients. Surgery. 1997;122:1132-1136.[EL 3]

118. Walz MK, Peitgen K, Walz MV, et al. Posterior retro-peritoneoscopic adrenalectomy: lessons learned within five years.World J Surg. 2001;25:728-734. [EL 3]

119. Allolio B, Fassnacht M. Clinical review: adrenocorticalcarcinoma;clinicalupdate.J Clin Endocrinol Metab. 2006; 91:2027-2037. [EL 3]

120. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M.Prevalenceandnaturalhistoryofadrenal incidentalomas.Eur J Endocrinol. 2003;149:273-285. [EL 3]

121. Icard P, Goudet P, Charpenay C, et al.Adrenocorticalcarcinomas: surgical trends and results of a 253-patientseriesfromtheFrenchAssociationofEndocrineSurgeonsstudygroup.World J Surg. 2001;25:891-897. [EL 3]

122. Luton JP, Cerdas S, Billaud L, et al.Clinicalfeaturesofadrenocorticalcarcinoma,prognosticfactors,andtheeffectofmitotane therapy.N Engl J Med. 1990;322:1195-1201. [EL 3]

123. Ng L, Libertino JM.Adrenocorticalcarcinoma:diagnosis,evaluationandtreatment.J Urol. 2003;169:5-11. [EL 3]

124. Herrera MF, Grant CS, van Heerden JA, Sheedy PF, Ilstrup DM. Incidentally discovered adrenal tumors: aninstitutional perspective. Surgery. 1991;110:1014-1021. [EL 3]

125. Angeli A, Osella G, Alì A, Terzolo M. Adrenal inci-dentaloma: an overview of clinical and epidemiologicaldata from the National Italian Study Group. Horm Res.1997;47:279-283. [EL 3]

126. Valeri A, Borrelli A, Presenti L, et al.Laparoscopicadre-nalectomy: personal experience in 78 patients. G Chir.2001;22:185-189. [EL 3]

127. Suzuki K, Ushiyama T, Ihara H, Kageyama S, Mugiya S, Fujita K. Complications of laparoscopic adrenalec-

tomyin75patientstreatedbythesamesurgeon.Eur Urol.1999;36:40-47. [EL 3]

128. Cobb WS, Kercher KW, Sing RF, Heniford BT.Laparoscopic adrenalectomy for malignancy. Am J Surg.2005;189:405-411. [EL 3]

129. Gonzalez RJ, Shapiro S, Sarlis N, et al. Laparoscopicresectionofadrenalcorticalcarcinoma:acautionarynote[withdiscussion].Surgery. 2005;138:1078-1086. [EL 3]

130. Huang H, Fojo T.Adjuvant mitotane for adrenocorticalcancer—arecurringcontroversy.J Clin Endocrinol Metab.2008;93:3730-3732. [EL 4]

131. Lee JE, Evans DB, Hickey RC, et al.Unknownprimarycancerpresentingasanadrenalmass:frequencyandimpli-cationsfordiagnosticevaluationofadrenalincidentalomas.Surgery. 1998;124:1115-1122. [EL 3]

132. Lam Ky, Lo Cy. Metastatic tumours of the adrenal glands: a 30-year experience in a teaching hospital. Clin Endocrinol (Oxf). 2002;56:95-101. [EL 2]

133. Lenert JT, Barnett CC Jr, Kudelka AP, et al.Evaluationand surgical resection of adrenal masses in patientswith a history of extra-adrenal malignancy. Surgery.2001;130:1060-1067. [EL 3]

134. Kasperlik-Zeluska AA, Roslonowska E, Slowinska-Srzednicka J, et al.Incidentallydiscoveredadrenalmass(incidentaloma): investigation and management of 208 patients.Clin Endocrinol (Oxf). 1997;46:29-37. [EL 3]

135. Yun M, Kim W, Alnafisi N, Lacorte L, Jang S, Alavi A.18F-FDGPETincharacterizingadrenallesionsdetectedonCT or MRI. J Nucl Med. 2001;42:1795-1799. [EL 3]

136. Casola G, Nicolet V, vanSonnenberg E, et al.Unsuspectedpheochromocytoma:riskofblood-pressurealterationsdur-ingpercutaneousadrenalbiopsy.Radiology. 1986;159:733-735.[EL 3]

137. McCorkell SJ, Niles NL.Fine-needleaspirationofcate-cholamine-producingadrenalmasses:apossiblyfatalmis-take.AJR Am J Roentgenol. 1985;145:113-114. [EL 3]

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AmERICAN ASSOCIATION Of ClINICAl ......2 AACE/AAES Adrenal Incidentaloma guidelines, Endocr Pract. 2009;15(Suppl 1)WRITING COMMITTEE Cochairpersons Martha A. Zeiger, MD, FACS, FACE